The new and more expedient method developed for the synthesis of 2'-fluoro-beta-D-threo-dideoxy nucleosides was successfully extended to a series of new purine and pyrimidine analogues. Among the new pyrimidine analogues prepared, 1-(2,3-dideoxy-2-fluoro-beta-D-threo- pentofuranosyl)cytosine and its 5-fluorocytosine analogue displayed good anti-HIV activity. None of the uracil derivatives were active. Among the purines, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)-6- chloropurine behaved as a prodrug of the active hypoxanthine nucleoside after activation by adenosine deaminase. Finally, the weak anti-HIV activity of 9- (2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)guanosine was increased significantly when used in combination with inosine monophosphate dehydrogenase inhibitors such as tiazofurin or ribavirin. A number of ring-enlarged analogues of the anti-HIV-active fermentation product oxetanocin A have been synthesized with the intent of assessing the importance of the extra hydroxymethyl side chain to the anti-HIV activity. Some of the resulting dideoxyapiose and carbocyclic nucleosides made represent new chemical structures. Their biological evaluation is in progress. 6-Substituted-2'-fluoro-dideoxy purine nucleosides which are substrates for adenosine deaminase (ADA) are being synthesized as prodrug forms of F-ddI and F-ddG. The in vitro anti-HIV activities of the 6-chloro and N6-methylamino analogues were found to be abolished by the ADA inhibitor, 2'-deoxycoformycin, and augmented by the addition of ADA to the culture medium. These prodrugs are being designed as lipophilic molecules with potential for transport to HIV sanctuaries, such as the CNS, prior to activation by ADA.